Synthetic pathways to create asymmetric center at C1 position of 1-substituted-tetrahydro-β-carbolines – a review

The 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indoles or tetrahydro-β-carbolines (THβCs) are tricyclic compounds that are found in various natural sources that exhibit a wide range of important pharmacological activities. Chiral 1-substituted-THβCs, which have an asymmetric center at C1, have attained significant interest due to their possible Monoamine Oxidase (MAO) inhibitory activity, benzodiazepine receptor binding activity, and antimalarial effectiveness against chloroquine-resistant Plasmodium falciparum. This review highlights and summarizes various novel stereoselective approaches to introduce chirality at the C1 position of 1-substituted-THβCs in good yield and enantiomeric excess (ee) or diastereomeric excess (de). These methods include the Pictet–Spengler reaction, chiral auxiliary, Asymmetric Transfer Hydrogenation (ATH) with chiral catalysts, asymmetric addition reaction, and enzymatic catalysis. The syntheses of chiral THβCs are reviewed comprehensively, emphasizing their role in drug development from 1977 to 2024.


Introduction
The tetrahydro-b-carbolines (THbCs) are a group of compounds found in a variety of natural and synthetic compounds containing a unique tricyclic pyrido [3,4-b]indole ring and renowned for their promising biological actions.Originating from tryptamine or tryptophan, these compounds are widespread in nature and have been isolated from various sources including plants, fungi, animals, and marine organisms. 1THbCs exhibit a broad spectrum of pharmacological activities; including phosphodiesterase 5 (PDE5)-inhibitory, 2 antitumor, 3,4 antiviral, 5,6 and antiprotozoal 7 especially antimalarial effects. 8,9hiral 1-substituted-THbCs 1 (Fig. 1), having an asymmetric center present at the C1 position, are still being sought even aer being discovered more than a hundred years ago. 10They are mainly MAO inhibitors or work by binding to benzodiazepine receptors. 11,12They have gained particular interest due to their potential antimalarial efficacy against a Plasmodium falciparum strain (FcB1-Colombia) that is chloroquine-resistant. 13ome of the specic 1-substituted-THbCs (Fig. 1) that have biological importance are given below: Justine 2 (HR22C16) induces mitotic arrest and blocking cell division in taxol-resistant cancer cells. 4,14he African rhacophorid frog Kassina senegalensis 15 is the source of trypargine 3a, a highly poisonous THbC alkaloid.It was recently discovered in a hitherto unknown ground ascidian Eudistoma sp. 16A very similar chemical, 6-hydroxy-trypargine, was shown to be a strong neurotoxic in the venom of the Brazilian web spider Parawixia bistriata. 17adalal 4 is an orally active PDE5 inhibitor and also highly potent. 2,18incamine 5 aided in mild to moderate dementia patients. 19ohimbine 6, an a 2 -adrenoceptor blocker that helps in erectile dysfunction. 20,21adiffine 7 collected from Vinca difformis. 22jmalicine 8 (ref.23) and reserpine 10 (ref.24) (Scheme 1) used as an antihypertensive.
Neonaucleoside C 9 collected from Neonauclea sessilifolia. 25umitremorgins are found in fungi that have antiviral 26 and cell-cycle inhibitory activities. 27They also worked as protein kinase and topoisomerase II inhibitors. 28ynthetic methodologies to introduce chirality at the C1 position in THbCs have been extensively studied. 29These methods include the Pictet-Spengler reaction, 30 asymmetric alkylation using N2-auxiliary as a directing group, 31 and acidinduced epimerization in conjunction with the Pictet-Spengler reaction. 32Additionally, the Bischler-Napieralski reaction 33 and classical Noyori ATH conditions 34 have been highlighted as key synthetic routes to create chiral 1-substituted-THbCs.The C1 stereocenter in THbCs plays a crucial role in their pharmacological properties, inuencing their activity in various therapeutic areas.With a ubiquitous presence in both natural sources and synthetic derivatives, these compounds have signicant attention in medicinal chemistry for their potential therapeutic applications.The intricate interplay of their chemical structure and biological effects underscores their pivotal role in drug discovery endeavors, accentuating the paramount importance of advancing synthetic methodologies to access these compounds efficiently.
In the last 11   [35][36][37][38][39] but our review does not comprise any of the above-mentioned perspective wholeheartedly.This review neither talks about pharmacological importance, nor biological activities; neither gives all of the synthetic methodologies, nor the applications of THbCs also.
With NaH and protic methanol (MeOH), Dieckmann cyclization of 22a and 22b gave the b-keto ester 23a and 23b and their enolic form 24a and 24b.These esters were hydrolyzed and decarboxylated by heating at 130 °C with NaCl and H 2 O in N,N-dimethylformamide (DMF) 50 producing the bridged ketone 25a (>95% ee) and 25b.
Then at −2 °C, the lowest temperature at which the solvent remained liquid, 50 and 100 eq. of water produced similar ee (92-93%) with increasing yields (91 and 99% respectively).Decreasing (S)-Proline to 3 mol% did not decrease the yield, but increasing water from 2 to 10 eq. at RT increased ee from 4 to 60%; and increasing water to 50 eq.at −2 °C required 23 hours to get 99% yield with 94% ee (Scheme 31).
Aer that, steric hindrance in the aliphatic chain of the aldehyde was increased by the use of 3-methylbutanal instead of butanal.Improved 12-77% conversion and 88 to >98% ee was seen for (1R)-123d compared to (1R)-123b.

Conclusion
Novel natural and synthetic THbC products continued to be discovered, with ongoing exploration of their biological activity directly related to the C1 chiral center.1-Substituted-THbCs and their derivatives have diverse biological actions, indicating that they are a promising drug scaffold for treating various diseases.We discussed ve synthetic methods with the purpose for creating C1 chiral center.For Pictet-Spengler reaction, the highest yield 99% and >97% ee was found from modied Pictet-Spengler reaction for formal syntheses of (−)-suaveoline, (−)-raumacline, and (−)-N b -methylraumacline intermediates; for chiral auxiliary, the highest 97% yield and highest 91% ee was reported from asymmetric synthesis of 1-substituted-THbC using pyroglutamic acid derivatives; for ATH with chiral catalysts, the highest afforded 92% yield and highest >98% ee was observed from ATH to synthesize 1-alkyl-1,2,3,4-tetrahydropyrido [3,4-b]indole; for asymmetric addition reaction, the highest 91% yield and 96% ee was recorded from synthesis of enantiomer of dihydrocorynantheol; for enzymatic catalysis, the highest conversion of 95% with >98% ee was obtained from stereoselective condensation by STR from Rauwola serpentina.
The methods that we have discussed here are the most used and widely found pathways for creating C1 chirality which is crucial for prominent biological activities.More efficient and economically feasible pathways should be revised so they could be applied for synthesizing new promising THbCs.
years, Laine et al., Maity et al., Szabó et al., Wang et al., and Du et al. published reviews that emphasized on the pharmacological importance, overall synthetic methods, biological activities, and applications of THbCs,

Scheme 18
Scheme 18 Reducing to THbC and removing N9 protection.

Example 2 .
Scheme 21 Removal of chiral auxiliary and protecting N-2, cyclization of the fourth ring, removal of N-9 protection.

Scheme 31
Scheme 31 Screening of solvent, temperature, and time.

Scheme 35
Scheme 35 Synthesizing enantiomer of dihydrocorynantheol by (S)proline catalyzed asymmetric addition reaction in four steps.